Analysis of Mice Lacking the Heparin-Binding Splice Isoform of Platelet-Derived Growth Factor A

Abstract

ABSTRACT Platelet-derived growth factor A-chain (PDGF-A) exists in two evolutionarily conserved isoforms, PDGF-A long and PDGF-A short , generated by alternative RNA splicing. They differ by the presence (in PDGF-A long ) or absence (in PDGF-A short ) of a carboxy-terminal heparin/heparan sulfate proteoglycan-binding motif. In mice, similar motifs present in other members of the PDGF and vascular endothelial growth factor (VEGF) families have been functionally analyzed in vivo , but the specific physiological importance of PDGF-A long has not been explored previously. Here, we analyzed the absolute and relative expression of the two PDGF-A splice isoforms during early postnatal organ development in the mouse and report on the generation of a Pdgfa allele ( Pdgfa Δex6 ) incapable of producing PDGF-A long due to a deletion of the exon 6 splice acceptor site. In situations of limiting PDGF-A signaling through PDGF receptor alpha (PDGFRα), or in mice lacking PDGF-C, homozygous carriers of Pdgfa Δex6 showed abnormal development of the lung, intestine, and vertebral column, pinpointing developmental processes where PDGF-A long may play a physiological role.